Bioequivalence assessment of topical clobetasol propionate products using visual and chromametric assessment of skin blanching

Abstract

-PURPOSE. The assessment of the degree of skin blanching following the application of a formulation containing a topical corticosteroid has been established as a surrogate method for the determination of bioequivalence. In this study, both visual and chromametric assessments have been carried out on two topical creams containing clobetasol propionate (0.05%) and the results from both methods are compared. METHODS. Human subjects (volunteers) were screened using a cream containing 0.05% clobetasol propionate, in order to identify appropriate subjects for inclusion in the study. The study was implemented according to the FDA guidance using both visual and chromameter assessment techniques. Blanching responses were assessed visually by three trained, independent observers and instrumentally using a Chromameter ® . An ED 50 of 36 min was used as the dose duration based upon data previously obtained from a pilot study using the same topical corticosteroid reference product. A visual rating scale of 0-4 and the a-scale readings from the chromameter were used. RESULTS. The visual and chromameter blanching profiles showed similar blanching responses with good correspondence. The 90% confidence intervals for the data from both methods were calculated using Locke's method. When only the data obtained from 23 subjects who were identified as "detectors" (as per FDA guidance) were used, the products fell within the bioequivalence acceptance range of 80-125% using the visual assessment method (99.3-111.6%) whereas the data using a chromameter (86.5-129.3%) were just outside the acceptance limits. However, when all subjects (n=34) were included in the calculations, both the visual (97.9-109.2) and chromameter (90.2-120.7) data fell within the bioequivalence acceptance range. CONCLUSIONS. Whereas visual data indicated bioequivalence using either data from "detectors" or data from all subjects, the chromameter data from "detectors" only indicated bioinequivalence but inclusion of all subject data fell within the acceptance range to be declared bioequivalent.

Comparison of tape stripping with the human skin blanching assay for the bioequivalence assessment of topical clobetasol propionate formulations.

“…AUC test /AUC ref ratios obtained from the abovementioned pilot study TS profiles indicated that the test and reference product showed the same outcome as that found with data previously obtained using the HSBA (Table 1)to assess identical products (21). On the basis of these data, pivotal TS studies were undertaken as described in section 2.3 using 30 subjects to provide a power of at least 80%.…”

“…The same formulation, Dermovate ® cream, was used as the reference and test product. TS data were compared with data obtained from an HSBA study (21) on the same product.…”

Strategies for the Bioequivalence Assessment of Topical Dermatological Dosage Forms

“…Upon comparing the product to itself, the results of AUC corr values showed similar confidence intervals and AUCtest/AUCref ratios using untransformed (Locke's) and also log-transformed data as shown in Table 2. It is interesting to note that the results are similar to those of a previously conducted pivotal HSBA study (Au et al, 2008). Hence, the TS method is seen to be comparable to the HSBA method, as it produced the same bioequivalence outcome.…”

“…The skin blanching profiles shown below were very similar when comparing the data between the two different assessment methods, or between "detectors" and "nondetectors" (Au et al, 2008).…”

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“…However, with respect to sampling of drug molecules from the skin, perturbation of blood flow to the local tissue is critical which would recover to normal in approximately two hours. The technique has been successfully adopted and demonstrated for dermatological research as well as for demonstrating the bioequivalence of topical dosage forms [19]. Dermal Microdialysis (DMD) is a relatively new application of microdialysis which allows continuous monitoring of endogenous and/or exogenous solutes in the interstitial fluid (ISF) of dermal tissue with minimal tissue trauma and involves the placement of small perfused membrane systems at given depths within the dermis.…”